title: Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo.
abstract: Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7(YFP+) TECs) reside within a subset of CD205(+)Ly51(+)CD40(low) cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80(+)CD40(high) mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7(YFP+) TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7(YFP+) TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7(YFP+) TECs dissociates from the receptor activator of NF-κB-mediated differentiation of CD80(+) mTECs. Still, Il7(YFP+) TECs can generate some CD80(+) mTECs in a stepwise differentiation process via YFP(-)Ly51(low)CD80(low) intermediates. Il7(YFP+) TECs are sustained in Rag2(-/-) mice, even following in vivo anti-CD3ε treatment that mimics the process of pre-TCR β-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2(-/-) TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7(YFP+) TECs, whereas negative selection provokes a striking loss of Il7(YFP+) TECs. These results imply that the strength of MHC/peptide-TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7-expressing cTECs.
authors.affiliation: Infection and Immunity Unit, CAGE Laboratory, Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Ribeiro
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Rodrigues
authors.forename: Catarina
authors.initials: C
authors.lastname: Meireles
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.forename: Nuno L
authors.initials: NL
authors.lastname: Alves
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D002135:Calcium-Binding Proteins; D056668:Cathepsin L / Q000096:biosynthesis; D002403:Cathepsins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009924:Organ Culture Techniques; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis / Q000378:metabolism; D054388:Receptors, CCR / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis; D060168:Thymocytes / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D000096927:AIRE Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D018122:B7-1 Antigen; D017252:CD3 Complex; D019013:CD40 Antigens; D002135:Calcium-Binding Proteins; D056668:Cathepsin L; D002403:Cathepsins; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D053246:Receptor Activator of Nuclear Factor-kappa B; D054388:Receptors, CCR; D011956:Receptors, Cell Surface; D012697:Serine Endopeptidases; D014157:Transcription Factors; D000096927:AIRE Protein; C491541:Ccl25 protein, mouse; C093569:DEC-205 receptor; C519665:DLL4 protein, mouse; C499308:Rag2 protein, mouse; C505687:Tnfrsf11a protein, mouse; C472501:Prss16 protein, mouse; C534278:Ctsl protein, mouse; C028217:cathepsin S